POS0452 ABNORMALITY OF TYPE I INTERFERON SIGNALLING IN B CELLS IN PRIMARY SJÖGREN´S SYNDROME AND THE IMPACT ON LABORATORY AND CLINICAL FINDINGS
Authors: J. Ritter, F. Szelinski, A. Aue, A. L. Stefanski, E. Schrezenmeier, T. Dörner
Journal: Annals of the Rheumatic Diseases (2022)

Background B cell hyperactivity (1), autoantibody production (anti-SS-A, anti-SS-B) and hypergammaglobulinaemia as well as interferon (IFN) signature (2) play a central role in the pathogenesis of primary Sjögren´s Syndrome (pSS). The link between these hallmarks is still elusive. While treatment of pSS remains limited, an improved understanding of IFN and JAK/STAT signalling on B cells may hold promise to improve potential treatment targets and related biomarkers. Objectives To investigate downstream molecules of the IFN signalling pathway on B cells and their clinical impact in pSS. Methods Peripheral blood from 47 pSS patients and 36 matched healthy controls (HC) was obtained and permeabilized for intracellular staining. Here B and T cell markers were applied together with Signal Transducers and Activators of Transcription 1 (STAT1), STAT2, pSTAT1 and 2, Interferon Regulatory factor 9 (IRF9), IRF7 and IRF1 and analysed by using flow cytometry. Cell subsets and correlations with all markers and clinical information were subjected to statistical analyses. Results Compared to HC the pSS group showed significantly elevated STAT1 expression among all B cell subsets (p&gt;0.0001) including naïve (CD27-IgD+), pre-switched (CD27+ IgD+), switched-memory (CD27+IgD-), double negative (CD27- IgD-) B cells and plasmablasts (CD27++ CD38++). Furthermore, IRF9 and STAT2 were increased among most B cell subsets. Positive correlations were found between STAT1 and IRF9 with Siglec-1 (CD169), an IFN signature marker expressed on the surface of CD14+ monocytes (p&gt;0.0001; r=0.633). Notably, increased levels of IRF9 positively correlates with STAT1. Upregulated STAT1 and IRF9 within pSS B cells were associated to extraglandular manifestations, high anti-SS-A and anti-SS-B autoantibodies, high anti-nuclear antibody titers (ANA) and rheumatoid factors (IgA, IgM) in pSS patients. Patients treated with prednisolone showed dose dependent inverse correlations of IRF9 expression among naïve-, memory-, and double negative B cells suggesting its treatment responsiveness. Conclusion The current data provide evidence of type I IFN on B cell subsets in pSS. Elevated STAT1, STAT2 and IRF9 expression suggest transcriptionally activity, which was evident in patients with extraglandular manifestations and elevated serologic activity. Targeting JAK/STAT in pSS could be beneficial for patients with high STAT1 levels leading to a personalized approach for this specific subgroup of patients. References [1]Nocturne G, Mariette X. B cells in the pathogenesis of primary Sjögren syndrome. Nature Reviews Rheumatology. 2018;14(3):133-45. [2]Brkic Z, Maria NI, Helden-Meeuwsen CGv, Merwe JPvd, Daele PLv, Dalm VA, et al. Prevalence of interferon type I signature in CD14 monocytes of patients with Sjögren’s syndrome and association with disease activity and BAFF gene expression. Annals of the Rheumatic Diseases. 2013;72(5):728-35. Disclosure of Interests None declared.